{"doi":"10.3390/cancers16193286","title":"Impact of Optimized Ku–DNA Binding Inhibitors on the Cellular and In Vivo DNA Damage Response","abstract":"Background: DNA-dependent protein kinase (DNA-PK) is a validated cancer therapeutic target involved in DNA damage response (DDR) and non-homologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). Ku serves as a sensor of DSBs by binding to DNA ends and activating DNA-PK. Inhibition of DNA-PK is a common strategy to block DSB repair and improve efficacy of ionizing radiation (IR) therapy and radiomimetic drug therapies. We have previously developed Ku–DNA binding inhibitors (Ku-DBis) that block in vitro and cellular NHEJ activity, abrogate DNA-PK autophosphorylation, and potentiate cellular sensitivity to IR. Results and Conclusions: Here we report the discovery of oxindole Ku-DBis with improved cellular uptake and retained potent Ku-inhibitory activity. Variable monotherapy activity was observed in a panel of non-small cell lung cancer (NSCLC) cell lines, with ATM-null cells being the most sensitive and showing synergy with IR. BRCA1-deficient cells were resistant to single-agent treatment and antagonistic when combined with DSB-generating therapies. In vivo studies in an NSCLC xenograft model demonstrated that the Ku-DBi treatment blocked IR-dependent DNA-PKcs autophosphorylation, modulated DDR, and reduced tumor cell proliferation. This represents the first in vivo demonstration of a Ku-targeted DNA-binding inhibitor impacting IR response and highlights the potential therapeutic utility of Ku-DBis for cancer treatment.","journal":"Cancers","year":2024,"id":469334,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9654,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1303073,"name":"Narva Deshwar Kushwaha","orcid":null,"position":1,"is_corresponding":false},{"id":1303074,"name":"Dineshsinha Chauhan","orcid":null,"position":2,"is_corresponding":false},{"id":1303075,"name":"Karim Ben Ali Gacem","orcid":null,"position":3,"is_corresponding":false},{"id":335359,"name":"Joy Garrett","orcid":null,"position":4,"is_corresponding":false},{"id":335357,"name":"Joseph R. Dynlacht","orcid":null,"position":5,"is_corresponding":false},{"id":1212482,"name":"Jean‐Baptiste Charbonnier","orcid":"0000-0002-5219-1983","position":6,"is_corresponding":false},{"id":333350,"name":"Navnath S. Gavande","orcid":"0000-0002-2413-0235","position":7,"is_corresponding":false},{"id":333355,"name":"John J. Turchi","orcid":"0000-0001-5375-2992","position":8,"is_corresponding":false},{"id":1302675,"name":"Pamela L. Mendoza-Munoz","orcid":"0000-0002-7416-9875","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:05:28.027781Z","pmid":"39409907","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}